Construction of New Safe, Efficient and in vivo Quaternary Ammonium Salt Antibacterial Agents through Chemical Modification

Quaternary ammonium compounds (QACs) are not only widely used in medical fields, such as pre-operative disinfection, wound cleaning, mucosal and non-critical surface disinfection, etc., but are also used in thousands of consumer products, such as hand sanitizers, cosmetics and body washes daily chemical products. The widespread use and large amounts of QACs released into the environment have raised concerns about their potential risks. More and more studies indicate its potential adverse effects on the body. What's more serious is that high doses of QAC have strong acute toxicity in the body. Therefore, QAC can only be used for surface disinfection or body surface disinfection and cannot be used inside the body.

In addition, bacterial infections in the human body can cause immune response disorders, eventually leading to organ dysfunction or even organ failure, posing a major threat to life. In clinical practice, strong antibiotic combination treatment is usually used, but antibiotics act slowly and have limited antibacterial spectrum, and patients are prone to drug resistance. In contrast, QAC directly disrupts bacterial membranes, rapidly eliminating a wide range of bacteria and fungi without developing drug resistance. If the scientific question of the acute toxicity of QACs can be resolved, its application in the treatment of infections in vivo will be better.

Therefore, in order to improve the antibacterial activity and biosafety of QAC, new research recently reported a new strategy to improve the antibacterial activity and biosafety of quaternary ammonium salt disinfectants through chemical structure modification. Based on the chemical structure of benzalkonium bromide (BB), a common quaternary ammonium salt compound, its long alkyl chain is replaced with a phthalocyanine group while retaining the benzyl or phenyl group of the benzalkane, and a new class of phthalocyanine-containing QACs (PACs) was constructed. A comprehensive and systematic evaluation of the antibacterial activity and biosafety of PAC was conducted. PAC was comprehensively characterized through modern molecular techniques, and it was explored that PAC has better antibacterial activity in vitro compared with QAC. It also proved that PAC can reduce the acute toxicity to blood cells and endothelial cells and elaborated on the biological mechanism. Finally, The PAC constructed by this strategy was applied to a mouse in vivo infection sepsis model, and the therapeutic effect was comprehensively evaluated.

First, based on the structure of a typical QAC: benzalkonium bromide (BB), while retaining the phenyl (or benzyl) group, the long alkyl side chain of the QAC was replaced with a highly hydrophobic phthalocyanine group to design 5 PACs with different chain lengths and aromatic rings were obtained. The intermediates form final products PACs through reactions such as methylation reactions.

The in vitro antibacterial activity test results of PAC showed that all PACs could effectively inhibit the growth of Escherichia coli or Staphylococcus aureus. At the same time, experiments clearly show that PAC1a plays a role in disinfecting skin and wounds, inhibiting infection, and promoting wound healing.

Based on PAC1a's powerful antibacterial activity and significantly reduced acute toxicity, experimental treatment with vancomycin or PAC1a significantly reduced the bacterial load in the body, and PAC1a's antibacterial efficiency was higher.

Reference

1. From disinfectants to antibiotics: enhanced biosafety of quaternary ammonium compounds by chemical modification
   Journal of Hazardous Materials, 2023, 460, 132454.